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Atopic dermatitis is a chronic inflammatory skin condition that affects approximately 18 million people in the United States. Assessing the extent and severity of atopic dermatitis is critical for determining baseline disease burden and treatment effectiveness for both investigators and clinicians. Considerable efforts over the past several decades have been made in developing a highly validated instrument called the Eczema Area and Severity Index (EASI). Although several guides exist for the EASI, questions continue to arise regarding its use and interpretation. This review was developed to serve as the definitive guide for the EASI and to address commonly asked questions.

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: By leveraging data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) and the Atopic Dermatitis Research Network (ADRN), we aim to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum (N=21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. For details, please see the Methods section in this article’s Online Repository at www.jacionline.org. RESULTS: We identified six loci at genome-wide significance (P

Atopic dermatitis (AD) has increased in prevalence to become the most common inflammatory skin condition globally, and geographic variation and migration studies suggest an important role for environmental triggers. Air pollution, especially due to industrialization and wildfires, may contribute to the development and exacerbation of AD. We provide a comprehensive, multidisciplinary review of existing molecular and epidemiologic studies on the associations of air pollutants and AD symptoms, prevalence, incidence, severity, and clinic visits. Cell and animal studies demonstrated that air pollutants contribute to AD symptoms and disease by activating the aryl hydrocarbon receptor pathway, promoting oxidative stress, initiating a proinflammatory response, and disrupting the skin barrier function. Epidemiologic studies overall report that air pollution is associated with AD among both children and adults, though the results are not consistent among cross-sectional studies. Studies on healthcare use for AD found positive correlations between medical visits for AD and air pollutants. As the air quality worsens in many areas globally, it is important to recognize how this can increase the risk for AD, to be aware of the increased demand for AD-related medical care, and to understand how to counsel patients regarding their skin health. Further research is needed to develop treatments that prevent or mitigate air pollution-related AD symptoms.

Background: Little is known about the burden of atopic dermatitis (AD) encountered in US primary care practices and the frequency and type of skin care practices routinely used in children. Objective: To estimate the prevalence of AD in children 0 to 5 years attending primary care practices in the United States and to describe routine skin care practices used in this population. Design: A cross-sectional survey study of a convenience sample of children under the age of 5 attending primary care practices for any reason. Setting: Ten primary care practices in 5 US states. Results: Among 652 children attending primary care practices, the estimated prevalence of ever having AD was 24% (95% CI, 21–28) ranging from 15% among those under the age of 1 to 38% among those aged 4 to 5 years. The prevalence of comorbid asthma was higher among AD participants compared to those with no AD, namely, 12% and 4%, respectively (P Conclusions: Our study found a large burden of AD in the primary care practice setting in the US. The majority of households reported skin care practices that may be detrimental to the skin barrier, such as frequent bathing and the routine use of moisturizers with high water: oil ratios. Clinical trials are needed to identify which skin care practices are optimal for reducing the significant burden of AD in the community.

BACKGROUND: While numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited. OBJECTIVES: This study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants. METHODS: AD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations. RESULTS: Genetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRS(AD): odds ratio [OR], 1.70; 95% CI, 1.49–1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRS(AD+): OR, 2.16; 95% CI, 1.89–2.47) and further improved when including FLG LOF mutations (PRS(AD++): OR, 3.23; 95% CI, 2.57–4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRS(AD++), which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77–5.36). CONCLUSIONS: This study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.

Background/Objectives: There is a paucity of validated tools for diagnosing atopic dermatitis (AD) in very young children that do not rely on clinical evaluation. The Childhood Eczema Questionnaire (CEQ)-a diagnostic tool for AD in children younger than 2 years that a caretaker can complete-was recently validated in Sweden. The objective of this study was to validate the tool in a U.S. population. As a substudy, we added an additional question that was independently assessed. Methods: Children younger than 2 years old were recruited from a dermatology clinic. Their caretakers completed a questionnaire containing the original tool's three questions as well as a fourth question that increased the time frame measured from 1 week to 6 months. Questionnaires with all "yes" answers were considered positive and were compared with a dermatologist diagnosis of AD. Results: A total of 283 subjects were recruited. The first three questions (the original CEQ) predicted a positive diagnosis of AD with a sensitivity of 0.72 (95% confidence interval [CI] 0.58, 0.82) and a specificity of 0.93 (95% CI 0.87, 0.95). In a separate analysis we included the first two questions and the fourth question and found that the sensitivity increased to 0.82 (95% CI 0.69, 0.90) with a specificity of 0.89 (95% CI 0.83, 0.93). Conclusion: This study validates a novel parental questionnaire for the diagnosis of AD in children younger than 2 years in a U.S. clinic population. (Less)

Interleukin-31 may play a role in the pathobiologic mechanism of atopic dermatitis and pruritus. We wanted to assess the efficacy and safety of nemolizumab (CIM331), a humanized antibody against interleukin-31 receptor A, in the treatment of atopic dermatitis.In this phase 2, randomized, double-blind, placebo-controlled, 12-week trial, we assigned adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments to receive subcutaneous nemolizumab (at a dose of 0.1 mg, 0.5 mg, or 2.0 mg per kilogram of body weight) or placebo every 4 weeks or an exploratory dose of 2.0 mg of nemolizumab per kilogram every 8 weeks. The primary end point was the percentage improvement from baseline in the score on the pruritus visual-analogue scale (on which a negative change indicates improvement) at week 12. Secondary end points included changes in the score on the Eczema Area and Severity Index (EASI, on which a negative change indicates improvement), and body-surface area of atopic dermatitis.Of 264 patients who underwent randomization, 216 (82%) completed the study. At week 12, among the patients who received nemolizumab every 4 weeks, changes on the pruritus visual-analogue scale were -43.7% in the 0.1-mg group, -59.8% in the 0.5-mg group, and -63.1% in the 2.0-mg group, versus -20.9% in the placebo group (P0.01 for all comparisons). Changes on the EASI were -23.0%, -42.3%, and -40.9%, respectively, in the nemolizumab groups, versus -26.6% in the placebo group. Respective changes in body-surface area affected by atopic dermatitis were -7.5%, -20.0%, and -19.4% with nemolizumab, versus -15.7% with placebo. Among the patients receiving nemolizumab every 4 weeks, treatment discontinuations occurred in 9 of 53 patients (17%) in the 0.1-mg group, in 9 of 54 (17%) in the 0.5-mg group, and in 7 of 52 (13%) in the 2.0-mg group, versus in 9 of 53 (17%) in the placebo group.In this phase 2 trial, nemolizumab at all monthly doses significantly improved pruritus in patients with moderate-to-severe atopic dermatitis, which showed the efficacy of targeting interleukin-31 receptor A. The limited size and length of the trial preclude conclusions regarding adverse events. (Funded by Chugai Pharmaceutical; XCIMA ClinicalTrials.gov number, NCT01986933 .).

Background Although epigenetic mechanisms are important risk factors for allergic disease, few studies have evaluated DNA methylation differences associated with atopic dermatitis (AD), and none has focused on AD with eczema herpeticum (ADEH+). We will determine how methylation varies in AD individuals with/without EH and associated traits. We modeled differences in genome-wide DNA methylation in whole blood cells from 90 ADEH+, 83 ADEH−, and 84 non-atopic, healthy control subjects, replicating in 36 ADEH+, 53 ADEH−, and 55 non-atopic healthy control subjects. We adjusted for cell-type composition in our models and used genome-wide and candidate-gene approaches. Results We replicated one CpG which was significantly differentially methylated by severity, with suggestive replication at four others showing differential methylation by phenotype or severity. Not adjusting for eosinophil content, we identified 490 significantly differentially methylated CpGs (ADEH+ vs healthy controls, genome-wide). Many of these associated with severity measures, especially eosinophil count (431/490 sites). Conclusions We identified a CpG in IL4 associated with serum tIgE levels, supporting a role for Th2 immune mediating mechanisms in AD. Changes in eosinophil level, a measure of disease severity, are associated with methylation changes, providing a potential mechanism for phenotypic changes in immune response-related traits. Electronic supplementary material The online version of this article (10.1186/s13148-019-0714-1) contains supplementary material, which is available to authorized users.

Atopic dermatitis (AD) is a T helper (Th)2-biased disease with elevated expression of Th2 cytokines that responds to Th2 signaling blockade. TRIM32 is an E3 ubiquitin ligase with innate antiviral activity. In our previous studies, we showed that Trim32 null mice developed Th2-biased skin inflammation in response to imiquimod and associated a low level of TRIM32 with AD. In this study, we provide evidence that TRIM32 deficiency contributes to enhanced Th2 cell differentiation in vitro. Analysis of TRIM32-associated proteins from public databases identified protein kinase C (PKC)ζ as a TRIM32-associated protein that contributes to the regulation of Th2 signaling. We demonstrated that PKCζ was specifically ubiquitinated by TRIM32 and, further, that PKCζ stability tended to be increased in Th2 cells with a Trim32 null background. Furthermore, Prkcz null mice showed compromised AD-like phenotypes in the MC903 AD model. Consistently, a high PKCζ and low TRIM32 ratio was associated with CD4+ cells in AD human skin compared with those in healthy controls. Taken together, these findings suggest that TRIM32 functions as a regulator of PKCζ that controls the differentiation of Th2 cells important for AD pathogenesis.

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease. There are no standardized methods for capturing long-term control of AD.ObjectiveWe sought to identify how long-term control has been captured in published randomized controlled trials (RCTs). Results will initiate consensus discussions on how best to measure long-term control in the core outcome set for AD.MethodsWe conducted a systematic review of RCTs of AD treatments published between 2000 and 2013, with a follow-up period of 3 months or longer, at least 1 outcome measure recorded at 3 or more time points, full article available, and published in English.ResultsIn all, 101 of 353 RCTs were eligible. Methods to capture long-term control included: repeated measurement of AD outcomes (92 RCTs; 91%), use of AD medication (29 RCTs; 28.7%), and AD flares/remissions (26 RCTs; 25.7%). Repeated measurements of AD outcomes were typically collected 3 to 5 times during a trial, but analysis methods often failed to make best use of the data. Time to first flare was most commonly used for trials including flare data (21/52). Medication use was recorded based on quantity, potency, and frequency of application.LimitationsWe included RCT data only.ConclusionThis review illustrates the difficulties in measuring long-term control, and points to the need for improved harmonization of outcomes.

Background Peripheral leukocytes in patients with atopic dermatitis (AD) have elevated phosphodiesterase-4 activity, which is associated with production of proinflammatory mediators. OPA-15406 is a phosphodiesterase-4 inhibitor with high selectivity for phosphodiesterase-4-B. Objectives We sought to assess effectiveness and tolerability of topical OPA-15406 in patients with AD. Methods This was a randomized, double-blind, vehicle-controlled, phase-II study. Patients 10 to 70 years of age with mild or moderate AD received topical OPA-15406 0.3% (n = 41), OPA-15406 1% (n = 43), or vehicle (n = 37) twice daily for 8 weeks. Results The primary end point, Investigator Global Assessment of Disease Severity score of 0 or 1 with greater than or equal to 2-grade reduction, was met at week 4 in the OPA-15406 1% group ( P = .0165 vs vehicle). Mean percentage improvement from baseline Eczema Area and Severity Index score for OPA-15406 1% was notable in week 1 (31.4% vs 6.0% for vehicle; P = .0005), even larger in week 2 (39.0% vs 3.0%; P = .0001), and persisted for 8 weeks. Visual analog scale pruritus scores improved from moderate to mild within the first week in the OPA-15406 1% group (36.4% mean change; P = .0011). OPA-15406 levels in blood were negligible. Incidence of adverse events was low, with most events mild in intensity. Limitations Further confirmatory phase-III studies are required. Conclusion OPA-15406 ointment may provide an effective therapeutic modality for patients with mild to moderate AD.

Background Atopic dermatitis (AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety. Methods This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected. Results Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years (N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar. Conclusions This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD.

BACKGROUND Dust mites (DMs) play a role in type I respiratory allergy. Studies relating to DM irritant versus immune reactions are somewhat conflicting in atopic dermatitis (AD). OBJECTIVE The aim of this study was to assess the diagnostic use of patch testing to DM in patients with AD and other dermatitides. METHODS We performed a prospective study of 323 adults recruited in a patch testing clinic. Patch testing antigens were DM extract (0.01%, 0.1%, 1%, 10%, and 20% in petrolatum; Chemotechnique) and/or 200 index of reactivity in petrolatum (Stallergenes). Patches were placed and read at 48 hours with delayed readings after 72 to 168 hours. RESULTS There was no association of DM positivity with AD, asthma, hay fever, or demographic factors. There was no association of DM positivity with the clinical diagnosis or phenotype. The number of positive (+, ++, and +++) and doubtful reactions to Chemotechnique DM extract increased with higher concentrations. Positive reactions to DM had a morphological appearance characterized by numerous discrete erythematous papules and, rarely, papulovesicles. Positive reactions to Stallergenes DM 200 IR were infrequent and all weak reactions, similar to DM 0.01%. CONCLUSIONS Patch testing to DM does not seem to have clinical use for determining the etiology of dermatitis.

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long-term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

BackgroundA subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype.ObjectiveWe sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+.MethodsWe performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis.ResultsWe identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency

High-risk human papillomavirus (hrHPV) infection is more likely to persist and cause cervical cancer in immunosuppressed women. Atopic dermatitis, which is known to affect cell-mediated immunity and skin barrier function, is associated with recalcitrant warts; therefore, we hypothesized that women with atopic dermatitis may be more likely to be positive for hrHPV infection and progress to high-grade cervical dysplasia.A retrospective case-control study of 1,160 women who were either positive or negative for hrHPV in their index cervical cytology. Patient age, race, history of atopic dermatitis, allergic rhinitis, smoking, body mass index, socioeconomic status, marital status, hormone contraceptive use, and 2-year clinical outcomes (follow-up hrHPV testing and cervical biopsy results) were recorded. All cases with atopic dermatitis (n = 74) were confirmed by a dermatologist. Analyses were restricted to females with documented clinical follow-up, which yielded 577 hrHPV-positive and 583 hrHPV-negative cases for comparison. Associations were examined by t test, χ test, and multivariate logistic regression.Atopic dermatitis was more common in the hrHPV-positive cases (48/577, 8.3%) compared with HPV-negative controls (26/583, 4.5%, p = .007). Multivariate logistic regression analysis revealed an adjusted odds ratio of 3.75 (95% CI = 1.3-10.9, p = .02) after controlling for significant covariates, such as age and marital status. Smoking was not associated with hrHPV infection, persistence, or high-grade cervical dysplasia in these cases.Atopic dermatitis is associated with cervical hrHPV infection in adult women.

SummaryBackground The Eczema Area and Severity Index (EASI) is an investigator-assessed instrument measuring the severity of clinical signs in atopic dermatitis (AD). The EASI was identified as one of the best-validated outcome measures for AD; however, no previous studies address how to interpret the EASI score for clinical use. Objectives To evaluate the interpretability and the ease of use of the EASI. Methods A retrospective analysis of paediatric and adult patients with AD was performed. Interpretability was evaluated by stratifying the EASI scores according to the Investigator's Global Assessment. The severity strata displaying the highest kappa coefficient of agreement were then selected as the recommended EASI band. The time to administer the EASI was recorded in a subgroup of patients. Results The suggested severity strata for the EASI are as follows: 0 = clear; 0·1–1·0 = almost clear; 1·1–7·0 = mild; 7·1–21·0 = moderate; 21·1–50·0 = severe; 50·1–72·0 = very severe (κ = 0·75). The EASI was also found to be acceptable in terms of ease of use, with assessments by trained investigators taking approximately 6 min. Conclusions Our study provides the first guide for interpreting the EASI score. It enables translation of the EASI numerical output into an AD global severity state that should be more meaningful to providers and patients. Along with a short administration time, the EASI demonstrates adequate feasibility, further supporting its use in clinical trials.

Background Nemolizumab, an anti–IL-31 receptor A mAb, improved pruritus, dermatitis, and sleep in adults with moderate-to-severe atopic dermatitis that was inadequately controlled by topical treatments in a phase II, 12-week, randomized, double-blind, placebo-controlled study (part A; NCT01986933 ). Objective We sought to assess the long-term efficacy and safety of nemolizumab injected subcutaneously every 4 weeks (Q4W) or every 8 weeks (Q8W) in a 52-week, double-blind extension (part B). Methods During part B, patients continued the previous nemolizumab dose (0.1, 0.5, or 2.0 mg/kg Q4W or 2.0 mg/kg Q8W). Part B end points included percentage improvement from baseline in pruritus visual analog scale and dermatitis scores (including the Eczema Area and Severity Index). Results Overall, 216 of 264 patients completed part A, and 191 entered part B; 131 completed part B. In 153 patients randomized to nemolizumab in part A, improvement from baseline in pruritus visual analog scale score was maintained/increased from weeks 12 to 64, with greatest improvement in the 0.5-mg/kg Q4W group (percentage change from baseline at week 64: −73.0, −89.6, −74.7, and −79.1 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Improvement from baseline in dermatitis scores was also maintained/increased to week 64 (percentage change in Eczema Area and Severity Index score: −68.5, −75.8, −78.9, and −69.3 in the 0.1-, 0.5-, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively). Over 64 weeks, 83% to 89% had 1 or more adverse events, with no new safety concerns identified. Conclusion Nemolizumab for up to 64 weeks was efficacious and overall well tolerated in patients with moderate-to-severe atopic dermatitis inadequately controlled by topical therapy.

Patients with atopic dermatitis (AD) are commonly colonized with Staphylococcus aureus (AD S. aureus + ), but what differentiates this group from noncolonized AD patients (AD S. aureus – ) has not been well studied. To evaluate whether these two groups have unique phenotypic or endotypic features, we performed a multicenter, cross-sectional study enrolling AD S. aureus + (n = 51) and AD S. aureus – (n = 45) participants defined by the presence or absence of S. aureus by routine culture techniques and nonatopic, noncolonized control individuals (NA S. aureus – ) (n = 46). Filaggrin ( FLG ) genotypes were determined, and disease severity (Eczema Area and Severity Index, Rajka-Langeland Severity Score, Investigator's Global Assessment score, Numerical Rating Scale, and Dermatology Life Quality Index) was captured. Skin physiology was assessed (transepidermal water loss [TEWL], stratum corneum integrity, hydration, and pH), and serum biomarkers were also measured. We found that AD S. aureus + patients had more severe disease based on all scoring systems except itch (Numerical Rating Scale), and they had higher levels of type 2 biomarkers (eosinophil count, tIgE, CCL17, and periostin). Additionally, AD S. aureus + patients had significantly greater allergen sensitization (Phadiatop and tIgE), barrier dysfunction (TEWL and stratum corneum integrity), and serum lactate dehydrogenase (LDH) than both the AD S. aureus – and NA S. aureus – groups. FLG mutations did not associate with S. aureus + colonization. In conclusion, adult patients with AD who are colonized on their skin with S. aureus have more severe disease, greater type 2 immune deviation, allergen sensitization, barrier disruption, and LDH level elevation than noncolonized patients with AD.

Atopic dermatitis therapy can be a challenge in many cases. Persistence into adulthood often reflects the more severe cases and such patients have the added problems of hand eczema and thick nummular lesions that resist topical medications. Within this group are patients labeled as having adult-onset atopic dermatitis, a designation that is hard to define and probably represents those whose childhood eczema was simply forgotten. Management is difficult for most adult cases and should not be diverted by questionable labels.

Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.

Background Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. Objective Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. Methods We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. Results Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient-related adverse events and no differences in adverse events between groups. Conclusion The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.

Streszczenie Wprowadzenie Atopowe zapalenie skory (wyprysk atopowy) jest przewleklą zapalną chorobą skory, ktora na calym świecie przybiera rozmiar epidemii wśrod dzieci, z ciągle zwiekszającą sie zachorowalnością. Z uwagi na istotny wplyw atopowego zapalenia skory spoleczno-ekonomiczny i na jakośc zycia chorych dzieci oraz ich rodzin, przez cale dekady prowadzono badania kliniczne skoncentrowane na zapobieganiu chorobie, z ograniczonym skutkiem. Ostatnie postepy wiedzy na temat biologii skory sugerują, ze zaburzenia bariery skornej mogą byc kluczowymi czynnikami inicjującymi atopowe zapalenie skory i byc moze uczulenie na alergeny. Cel Celem badania bylo sprawdzenie, czy wsparcie bariery skornej od urodzenia jest skuteczną strategią zmniejszenia czestości wystepowania atopowego zapalenia skory u noworodkow z wysokim ryzykiem. Metody Przeprowadzono w Stanach Zjednoczonych i Wielkiej Brytanii kontrolowane badanie kliniczne z randomizacją u 124 noworodkow z wysokim ryzykiem atopowego zapalenia skory. Rodzicow dzieci w ramieniu eksperymentalnym poinstruowano o stosowaniu na cale cialo środka zmiekczającego co najmniej raz dziennie, rozpoczynając w ciągu 3 tygodni od urodzenia. Rodzice w ramieniu kontrolnym byli proszeni o niestosowanie środkow zmiekczających. Glownym miernikiem wykonalności badania byl odsetek rodzin wyrazających zgode na randomizacje. Pierwszorzedowym wynikiem klinicznym byla skumulowana czestośc atopowego zapalenia skory po 6 miesiącach, oceniana przez wyszkolonego badacza. Wyniki Ogolem 42% kwalifikujących sie rodzin wyrazilo zgode na randomizacje do badania. Wszystkie rodziny uczestniczące w ramieniu eksperymentalnym uznaly badaną interwencje za akceptowalną. Wykazano statystycznie istotny efekt zapobiegawczy po codziennym stosowaniu środka zmiekczającego w zakresie skumulowanej czestości wystepowania atopowego zapalenia skory, ze zmniejszeniem ryzyka wzglednego o 50% (ryzyko wzgledne 0,50; 95% CI, 0,28–0,9; p = 0,017). Nie odnotowano zadnych dzialan niepoządanych związanych ze stosowaniem środka zmiekczającego, a takze zadnych roznic dotyczących dzialan niepoządanych pomiedzy grupami badanymi. Wnioski Wyniki badania wykazują, ze stosowanie środka zmiekczającego od urodzenia stanowi wykonalną, bezpieczną i skuteczną strategie zapobiegania atopowemu zapaleniu skory. Jeśli zostanie to potwierdzone w wiekszych badaniach, stosowanie środkow zmiekczających od urodzenia staloby sie prostą i niską kosztowo interwencją, pozwalającą na zmniejszenie globalnego rozprzestrzenienia chorob alergicznych.

Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.

Background Skin care remains a key component in atopic dermatitis (AD) management; there are no data available guiding optimal bathing recommendations. Objective This study aims to determine whether 15-minute to 20-minute baths followed by topical corticosteroid application (prehydration therapy) are effective for clearing moderate to severe AD. Methods In the Oregon Health & Science University outpatient dermatology clinic, a retrospective review was done of the health records of patients with AD seen first between January 1, 2007, and December 31, 2011, who were then reevaluated within 1 to 3 weeks of starting the therapy. Qualifying patients underwent the prehydration regimen and were reevaluated. The primary outcome was therapeutic response using the Investigators' Global Assessment Scale. Secondary outcomes were measured using the dynamic Treatment Response Scale. Of 110 distinct electronic records, 35 patients were excluded. At the initial visit, 75 patients were evaluated with the Investigators' Global Assessment Scale. Forty-eight patients (64%) were severe, and 27 patients (36%) were moderate. All subjects began prehydration therapy followed by topical corticosteroid. At follow-up visit in 1 to 3 weeks when using the patient's or provider's assessment of treatment response, 59 patients (79%) had marked improvement, and 3 patients (4%) were clear. Conclusions Prehydration followed by topical corticosteroid therapy seems to be a highly effective regimen that achieves rapid control of moderate to severe disease.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed.

Background Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. Objective We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. Methods In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. Results YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4 + T-cell responses was observed. Conclusions YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus.

Background Little is known about the epidemiology of eczema in adults. The goal of this study was to determine the prevalence of and associations with adult eczema in the United States. Methods We used the 2010 National Health Interview Survey from a nationally representative sample of 27,157 adults age 18 to 85 years. Results Overall, the 1-year prevalence of eczema was 10.2% (95% CI, 9.7% to 10.6%). The 1-year prevalence of eczema with asthma and/or hay fever was 3.2% (95% CI, 2.8% to 3.3%). Adult eczema was associated with higher prevalence of asthma ( P 2 test), more asthma attacks in the past year ( P P = .02). In multivariate models eczema prevalence was significantly higher in older participants; female subjects; those with Hispanic ethnicity, US birthplace, and higher level of household education; and those currently working (all P ≤ .02, logistic regression). Conclusions This study provides US population–based estimates of eczema prevalence and asthma associations in adults. The results suggest multiple demographic and socioeconomic influences on the US prevalence of adult eczema.

Atopic dermatitis (AD, also known as atopic eczema) is driven by a complex relationship between genetic predisposition and environmental exposures. We sought to determine the impact of specific climatic factors on the prevalence of AD in the United states. We used a merged analysis of the 2007 National Survey of Children’s Health (NSCH) from a representative sample of 91,642 children aged 0–17 years and the 2006–2007 National Climate Data Center and Weather Service measurements of relative humidity (%), indoor heating degree days (HDD), clear-sky UV indices, ozone levels, and outdoor air temperature. As a proxy for AD, we used an affirmative response to the NSCH survey question asking whether the participant’s child has been given a doctor diagnosis of “eczema or any other kind of skin allergy” in the previous 12 months. In multivariate models controlling for sex, race/ethnicity, age, and household income, eczema prevalence was significantly lower with the highest-quartile mean annual relative humidity (logistic regression, adjusted odds ratio (95% confidence interval)=0.82 (0.71–0.96), P=0.01) and issued UV index (0.73 (0.64–0.84), P

Subjects with atopic dermatitis (AD) have defects in antimicrobial peptide (AMP) production possibly contributing to an increased risk of infections. In laboratory models, vitamin D can alter innate immunity by increasing AMP production.To determine if AD severity correlates with baseline vitamin D levels, and to test whether supplementation with oral vitamin D alters AMP production in AD skin.This was a multi-centre, placebo-controlled, double-blind study in 30 subjects with AD, 30 non-atopic subjects, and 16 subjects with psoriasis. Subjects were randomized to receive either 4000 IU of cholecalciferol or placebo for 21 days. At baseline and day 21, levels of 25-hydroxyvitamin D (25OHD), cathelicidin, HBD-3, IL-13, and Eczema Area and Severity Index (EASI) and Rajka-Langeland scores were obtained.At baseline, 20% of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI, but not AD severity. After 21 days of oral cholecalciferol, mean serum 25OHD increased, but there was no significant change in skin cathelicidin, HBD-3, IL-13 or EASI scores.This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD, and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels. Given the molecular links between vitamin D and immune function, further study of vitamin D supplementation in subjects with AD is warranted.

Altered innate immunity is a feature of certain skin inflammatory diseases such as psoriasis and atopic dermatitis (AD). In this study, we provide evidence that deficiency in Trim32 (a tripartite motif [TRIM] protein with innate antiviral activity) contributes to a T helper type 2 biased response and predisposes to features of AD in mice. On treatment with the toll-like receptor 7 agonist imquimod (IMQ), Trim32 knockout mice displayed compromised psoriasiform phenotypes and defective T helper type 17 response. Instead, IMQ treatment of Trim32 knockout mice induced AD-like phenotypes with enhanced skin infiltration of eosinophils and mast cells, elevation of T helper type 2 cytokines/chemokines expression, and reduced expression of filaggrin protein expression. Furthermore, although the induction of phosphorylated Stat3 and RelA was compromised after IMQ treatment in the knockout mice, phosphorylated Stat6 was elevated. CC chemokine ligand 20 induction by tumor necrosis factor-α and IL-17A was reduced in Trim32-deficient keratinocytes, whereas CC chemokine ligand 5 induction by tumor necrosis factor-α and IL-4 was enhanced. In addition, Trim32 protein levels were elevated in mice treated with IMQ. Unlike Trim32 overexpression in psoriasis, TRIM32 levels were low in patients with AD. Based on Trim32 induction by IMQ, the lower levels of TRIM32 in AD skin compared with healthy control and psoriatic skin suggest a defective TRIM32 pathway in AD pathogenesis.

Allergic contact dermatitis (ACD) may complicate the clinical course of atopic dermatitis (AD), and patch testing remains the criterion standard for diagnosing ACD. To date, there have been no guidelines or consensus recommendations on when and how to patch test individuals with AD. Failure to patch test when appropriate may result in overlooking an important and potentially curable complicating comorbidity. In this article, we present consensus recommendations regarding when to perform patch testing in the AD patient, best practices, and common pitfalls. Patch testing should be considered in AD patients with dermatitis that fails to improve with topical therapy; with atypical/changing distribution of dermatitis, or pattern suggestive of ACD; with therapy-resistant hand eczema in the working population; with adult- or adolescent-onset AD; and/or before initiating systemic immunosuppressants for the treatment of dermatitis. A suggested patch testing algorithm for AD patients is provided.

Background Antibody responses to the inactivated seasonal influenza vaccine in patients with atopic dermatitis (AD) have not been carefully characterized. Objective The primary objective of this study was to compare antibody responses to intradermal vaccination in participants with moderate/severe AD with those in nonatopic participants. Secondary objectives were to evaluate the effect of route of administration, Staphylococcus aureus skin colonization, and disease severity on vaccine response. Methods This was an open-label study conducted in the 2012-2013 influenza season at 5 US clinical sites. A total of 360 participants with moderate/severe AD or nonatopic subjects were assessed for eligibility, 347 of whom received intradermal or intramuscular vaccination per label and were followed for 28 days after vaccination. The primary outcome was the difference in the proportion of participants achieving seroprotection (hemagglutination-inhibition antibody titer ≥1:40 on day 28 after vaccination). Results Seroprotection rates for influenza B, H1N1, and H3N2 were not different (1) between participants with AD and nonatopic participants receiving intradermal vaccination and (2) between AD participants receiving intradermal and intramuscular vaccination. After intradermal, but not intramuscular, vaccination, participants with AD with S aureus colonization experienced (1) lower seroprotection and seroconversion rates and lower hemagglutination-inhibition antibody titer geometric mean fold increase against influenza B and (2) lower seroconversion rates against influenza H1N1 than noncolonized participants with AD. Conclusion Participants with AD colonized with S aureus exhibited a reduced immune response to influenza vaccination compared with noncolonized participants after intradermal but not intramuscular vaccination. Because most patients with AD are colonized with S aureus , intramuscular influenza vaccination should be given preference in these patients.

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmo, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [ including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

Interferon regulatory factor 2 ( IRF2 ) is a member of a family of transcriptional factors involved in the modulation of IFN-induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of atopic dermatitis (AD) and ADEH (atopic dermatitis complicated by eczema herpeticum), we genotyped 78 IRF2 tagging single-nucleotide polymorphisms (SNPs) in both European-American ( n =435) and African-American ( n =339) populations. Significant associations were observed between AD and two SNPs (rs793814, P =0.007, odds ratio (OR)=0.52; rs3756094, P =0.037, OR=0.66) among European Americans and one SNP (rs3775572, P =0.016, OR=0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs ( P =0.049–0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a five-SNP (CAGGA) haplotype showed the strongest association with ADEH ( P =0.0008). Eight IRF2 SNPs were significantly associated with IFN-γ production after herpes simplex virus (HSV) stimulation ( P =0.048–0.0008), including an AD-associated SNP (rs13139310, P =0.008). Our findings suggest that distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.

Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.